Benzothiadiazine derivatives



Unite g -rates atetit hice 3,057,862 Patented Oct. 9, 1962 3,057,862BENZOTHIADHAZTNE DERIVATIVES Harry Louis Yale, New Brunswick, N.J.,assignor to Olin Mathieson Chemical Corporation, New York, N.Y., acorporation of Virginia No Drawing. Filed Mar. 25, 1959, Ser. No.801,691 3 Claims. (Cl. 260-243) This invention relates to newbenzothiadiazine derivatives, and more particularly to newtrifiuoromethylbenzothiadiazinesulfonamide derivatives, one tautomer ofwhich has the general formula e YNHSOz f Fa C-R as well as the alkalimetal salts thereof, wherein R is with either the acyl halide(preferably chloride) or acid anhydride of an acid of the formula:RCOOH, wherein R is as above defined to yield the new intermediates ofthis invention of the general formula I YNHSO SO21. HY

NHOOR wherein R is the R value of the acid reactant and the Ys are thesame or different and represent either hydrogen or the acyl radical ofthe acid reagent. The nature of the intermediate depends on theproportion of acid to sulfonamide. When a large excess of acid ispresent, a triacylated product (both Ys are RC0) is formed. If, however,four or less molar equivalents of acid or inner anhydride (or two orless molar equivalents of normal anhydride) are used, then a mixture ofthe mono- (both Ys are hydrogen) and di- (one Y is RC0 and the other ishydrogen) acylated derivatives are formed. In both instances, howeverthe reaction is preferably conducted at an elevated temperature belowabout 150 C.

Upon pyrolysis the intermediates of this invention cyclize to yield thefinal products of this invention. This pyrolysis is accomplished byheating the intermediate to a temperature above about 200 C. The natureof the final product will depend upon the degree of acylation of theintermediate. Thus, a triacylated intermediate will yield a productwherein Y is RCO, whereas the monoand diacylated intermediates bothyield a product wherein Y is hydrogen.

The sulfonamide reactants can be prepared as disclose in the applicationof Yale et al., Serial No. 698,377, filed November 25, 1957, now PatentNo. 3,040,042, granted June 19, 1962, and specifically include5-aInlIlO-a,a,octrifiuoro-2,4-toluenedisulfonamide,4-amino-a,a,a-trifiuoro-3,5-toluenedisulfonamide, and2-amino-a,a,a-trifluoro- 3,5-toluenedisulfonamide. Among the suitableacid reactants may be mentioned the acyl halides and particularly theacid anhydrides of the lower alkanoic acids of at least two carbon atoms(eg. acetic anhydride, propionic anhydride, butyric anhydride, valericanhydride, and enanthic anhydride) and the acyl halides and particularlythe inner anhydrides of the lower alkanedioic acids (e.g. succinicanhydride, glutaric anhydride, u-ethylsuccinic anhydride, andfi-methylglutaric anhydride).

The free benzothiadiazine products, thus formed, can then, if desired betreated with alcoholic alkali metal hydroxides (e.g. potassiumhydroxide), whereby the alkali metal salts are formed.

The following Examples illustrate the invention (all temperatures beingin centigrade):

EXAMPLE 1 3-Methyl-6-Trifluoromethyl-I,2,4-Benz0thiadiazine-7-Sulfonamide 1,1-Di0xide (a) Preparation of5-acetamido-u,u,a-triflu0r0-2,4-t0luensulfonamide and5-acetamid0-u,a,o-triflu0r0-4-acetamidosulfonyl2-t0luenesulfonamide.Amixture of 9.6 g. (0.03 mole) of 5-amino-a,x,a-trifluoro-2,4-toluenedisulfonamide, 6.12g. (0.06 mole) of aceticanhydride and 50 ml. of glacial acetic acid is refluxed for three hoursand then concentrated in vacuo fromthe steam bath. The residue is abrown glass which when warmed with 50 ml. of water solidifies. The solidis filtered and recrystallized from water to give a product having aM.P.

. of about 215-218" which represents a mixture of the monoacetyl anddiacetyl derivatives.

(b) Preparation of S-methyl-o-trifluoromethyl-l,2,4-benzorhiadiazine-7-sulf0namide ],1-di0xide.-The mixture obtained in step(a) is pyrolyzed by placing in an oil bath preheated to 200 and thenallowing the temperature to rise to 250 during two hours. The resultantsolid, upon recrystallization from water, gives about 3 g. of 3 methyl 6trifluoromethyl 1,2,4 benzothiadiazine- 7-sulfonamide 1,1-dioxide, M.P.about 338-340.

EXAMPLE 2 Dipozassium Salt of 3-Methyl-6-Triflu0r0methyl-1,2,4-Benzothiadiazine-7-Sulf0namicle 1 ,1 -Di0xide To a solution of 6.5 g. ofpotassium hydroxide in ml. of ethanol is added gradually with shaking17.2 g. of3-methyl-6-trifiuoromethyl-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide.The solid dissolves. The resulting alcoholic solution is concentrated invacuo to yield the dipotassium salt of 3-methyl-6-trifluoromethyl- 1,2,4benzothiadiazine-7-sulfonarnide 1,1-dioxide.

Similarly, using an equivalent quantity of sodium hydroxide instead ofpotassium hydroxide in the procedure of Example 2, the disodium salt isobtained. Furthermore, if only 3.25 g. of 85% potassium hydroxide isused in Example 2, the monopotassium salt is obtained.

EXAMPLE 3 3-Methyl-7-Triflu0rorrz ethyl-1,2,4-Benz0thiadiazine- 5-Sulf0namide 1,I-Di0xide Following the procedure of Example 1, butsubstituting 9.6 g. of 4-amino-oc,a,a-trifluoro-3,5-toluenedisulfonamidefor the 5-amino-a,a,a-trifluoro-2,4-toluenedisulfonamide, a mixture ofthe mono and diacetyl derivatives are first formed, from which3-methyl-7-trifluoromethyl-1,2,4- benzothiadiazine-S-sulfonamide1,1-dioxide is obtained.

3 EXAMPLE 4 3-Metlzyl-5-Trifluoromethyl-1,2,4-Benzothiadiazine-7-Salf0namide 1,1-Dixide Following the procedure of Example 1, butsubstituting 9.6 g. of 2-amino-a,u,a-trifluoro-3,S-toluenedisulfonamidefor the S-ZITILDO-05,06,Dt-ll'lflllOIO-2,4-t01l1ElledlSlllfOl'lZiDlidC,a mixture of the mono and diacetyl derivatives are first obtained fromwhich 3-methyl-5-trifiuoromethyl-1,2,4- benzothiadiazine7-sulfonamide1,1-dioxide is prepared.

EXAMPLE 3-Ethyl-d-Trifluoromethyl-1 ,2,4-Benzothiadiazine- 7-Sulfonamide1,1-Di0xide Following the procedure of Example 1, but substituting 7.8g. (0.06 mole) of propionic anhydride for the acetic anhydride and 50ml. of propionic acid the acetic acid in step (a), there is firstobtained a mixture of5-propionan1ido-oc,a,a-trifluoro-2,4-toluenedisulfonamide andS-propionarnido 0t,a,oc trifluoro 4 propionamidosulfonyl-Z-toluenesulfonamide, and then by the procedure of step (b),3-ethyl-6-trifiuoromethyl-l,2,4-benzothiadiazine- 7-sulfonamide1,1-dioxide.

Similarly, valeric anhydride and enanthic anhydride, substituted inequivalent amount, yield first a mixture of the 5-mono and 4,5-diacylated derivatives, and then 3 n butyl 6 trifiuoromethyl 1,2,4benzothiadiazine- 7-sulfonamide 1,1-dioxide and3-n-hexyl-6-trifluoromethyl-l,2,4-be11zothiadiazine-7-sulfonamide1,1-dioxide, respectively.

EXAMPLE 6 7-Snlfamyl-6-Trifluoromethyl-1,2,4-Benz0thiadiazine-3-Propionic Acid 1,1-Di0xide (a) Preparation offl-(2,4-disulfamyl-5-trifluorometlzylphenylcarbamyl)-propionic acid.-Amixture of 32 g. (0.1 mole) of5-amino-a,a,a-trifiuoro-2,4-toluenedisulfonamide, and g. (0.1 mole) ofsuccinic anhydride is fused for two hours in an oil bath maintained at175. The resultant product is recrystallized from water to give about 23g. of ;8(2,4-disulfamyl-S-trifiuoromethyl-phenylcarbamyl)propionic acid,MP. about 260-262".

(b) Preparation of 7-su[fan1yl-6-trifluoromethyI-J,2,4-bcnzotlziadiazine-S-propionic acid 1,1-dioxide.-23 g. offl-(2,4-disulfamyl-S-trifluoromethyl-phenylcarbamyl)propiouic acid isfused for one hour in an oil bath maintained at 240450". The product isdecolorized by refluxing with activated charcoal in 600 ml. of acetonesolution. The filtered acetone solution is concentrated to 150 ml. anddiluted with 600 ml. of Water. The product crystallizes to yield, afterdrying, about 6.7 g. of 7-sulfamyl-6-tritluoromethyl-l,2,4-benzothiadiazine-B-propionic acid 1,1-dioxide,MP. about 334335.

Similarly, by substituting an equivalent amount of glutaric anhydride,fi-methylglutaric anhydride, and uethylsuccinic 'anhydride for thesuccinic ahydride in step (a) of Example 6, there is first obtained'y-(2,4-disulfamyl- 5-trifiuoromethyl-phenylcarbamyl)butanoic acid;'y-(2,4- disulfamyl-S-trifluoromethyl-phenylcarbamyl)43 methyl butanoicacid, andfl-(2,4-disulfamyl-5-trifiuoromethylphenylcarbamyl)-a-ethylpropionicacid, respectively; and then by the procedure of step (b),7-sulfamyl-6-trifiuoromethyl-l,2,4-benzothiadiazine-3-butanoic acid, 7-sulfamyl 6 trifiuormethyl 1,2,4-benzothiadiazine-3-{3- methylbutanoicacid, and 7-sulfamyl-6-trifluoromethyl-1,2,4-benzothiadiazine-3-a-ethylpropionic acid, respectively.

EXAMPLE 7 7-AcetyIsulfamyl-3-Methyl-d-Trifluoromethyl-],2,4-Benzothiadiazine 1,1-Di0xide (a) Preparation of5-acetamido-u,a,a-triflzmro-ZA-diacezamidosulfonyltolueae.A mixture of25 g. (0.078 mole) of 5-arnino-a,a,a-trifluoro-2,4-toluenedisultonam- 4ide and g. (0.91 mole) of acetic anhydride is heated under reflux fortwo hours, cooled, and the crystalline solid filtered on a sitered glassfunnel. Recrystallization from aqueous acetonitrile (2:1) gives5-acetamido-u,a,atrifiuoro-2,4-diacetamidosulfonyltoluene, M.P. about200202.

(b) Preparation of7-acetylsulfamyl-3-methyl-6-trifluoromctIzyl-l,2,4-benzothiadiazine1,1-dioxide. 15 g. ofS-acetamidO-a,a,a-trifluoro-2,4-diacetamido-sulfonyltoluene is pyrolyzedfor two hours in an oil bath at 215- 225. The pyrolysis product isdissolved in 500 ml. of boiling acetone, this solution is decolorizedwith activated charcoal, filtered and the filtrate concentrated todryness. The residual white solid is recrystallized from aqueousisopropanol (1:1) to give about 4.5 g. of 7-acetylsulfamyl-3-methyl-6-trifiuoromethyl-1,2,4-benzothiadiazine, 1,1-di oxide, M.P.about 285-287.

EXAMPLE 8 3-Ethyl-o-Triflnoromethyl-1,2,4-Benzothiadiazine-7-Snlfonamide 1,1-Dioxide (a) Preparation of5-propi0namido-a,a,a-trifluoro-2,4- dip/opionamidosulfonyltoluene.Amixture of 25 g. (0.08 mole) ofS-aminO-a,a,a-trifiuoro-2,4-toluenedisulfonamide and 104 g. (0.8 mole)of propionic anhydride is heated under reflux for two hours and thenconcentrated to dryness. The crude product is recrystallized fromaqueous acetonitrile (9:1) to give an analytical sample of 5-propionamido-wwa trifluoro 2,4 dipropionamidosulfonyltoluene, M.P. about227-229".

(b) Preparation of3-ethyI-6-trifluorometlryl-1,2,4-benzolhiadiazine-7-sulfonamidel,1-di0xidc.31 g. of 5-propionamido-wa-a-trifluoro 2,4dipropionamido-sulfonyltoluene is dissolved in 310 ml. of Dowtherm Apreheated to 210. The solution is kept two hours at 210-215", cooled,and the crystalline solid filtered. The solid is washed with ethyletherand recrystallized from aqueous isopropanol (1:1) to give about 10 g. of3-ethyl-6-trifluoromethyl-1,2,4-benzothiadiazine-7- sulfonamide1,1-dioxide, M.P. about 345347 (dec.).

The invention may be variously otherwise embodied within the scope ofthe appended claims.

What is claimed is:

1. A compound selected from the group consisting of benzothiadiazines ofthe formula 3. 7-sulfamyl-6-trifiuoromethyl-1,2,4 benzothiadiazine-3-propionic acid 1,1-dioxide.

References Cited in the file of this patent UNITED STATES PATENTS2,191,432 Kharasch Feb. 20, 1940 2,240,496 Dvornikofi May 6, 19442,809,194 Novello Oct. 8, 1957 2,894,948 De Stevens July 14, 19592,910,475 Novello Oct. 27, 1959 2,910,476 Novello Oct. 27, 1959 OTHERREFERENCES Freeman et al.: Journ. Org. Chem, vol. 16, page 815 837, page818 relied on (1951).

Novello et al.: Journ. Amer. Chem. Soc., vol. 79, page 2028-9 (1957).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BENZOTHIADIAZINES OFTHE FORMULA